鹽酸特比萘芬片在犬體內(nèi)的藥動(dòng)學(xué)及絕對(duì)生物利用度研究
發(fā)布時(shí)間：2019-03-27 09:36
【摘要】：鹽酸特比萘芬是第二代丙烯胺類廣譜抗真菌藥,具有抗真菌機(jī)制明確、抗真菌譜廣、療效確切、劑型多、適用性廣等特點(diǎn),目前已在人醫(yī)臨床廣泛應(yīng)用,但在動(dòng)物方面的研究仍較少。本試驗(yàn)旨在通過對(duì)犬進(jìn)行鹽酸特比萘芬注射液注射和鹽酸特比萘芬片口服給藥,以獲得相關(guān)藥動(dòng)學(xué)參數(shù),了解特比萘芬在犬體內(nèi)的藥代動(dòng)力學(xué)過程及絕對(duì)生物利用度,為獸醫(yī)臨床制定合理的給藥方案及有效降低不良反應(yīng),提供理論依據(jù)。8只體重較一致的健康比格犬采用交叉試驗(yàn)設(shè)計(jì),隨機(jī)分為兩組,每組4只(公母各半)。第一階段,第一組犬單劑量(5 mg/kg bw)靜脈注射2%鹽酸特比萘芬注射液,第二組犬單劑量(20 mg/kg bw)口服鹽酸特比萘芬片;第二階段,第一組犬單劑量(20 mg/kg bw)口服鹽酸特比萘芬片,第二組犬單劑量(5 mg/kg bw)靜脈注射2%鹽酸特比萘芬注射液,兩階段洗脫期為2周。另設(shè)一平行較低劑量口服給藥組,即8只犬單劑量(10 mg/kg bw)口服鹽酸特比萘芬片。給藥后按預(yù)定時(shí)間采集血樣。血漿中特比萘芬含量采用高效液相色譜串聯(lián)二極管陣列檢測(cè)器(HPLC-DAD)進(jìn)行檢測(cè)分析,流動(dòng)相為甲醇-0.1%磷酸水溶液(59:41,V/V)。外標(biāo)法定量。特比萘芬的實(shí)測(cè)血藥濃度-時(shí)間數(shù)據(jù)采用WinNonlin5.2版藥動(dòng)學(xué)分析軟件計(jì)算藥代動(dòng)力學(xué)參數(shù)。單劑量(5 mg/kg bw)靜脈注射2%鹽酸特比萘芬注射液后,特比萘芬在犬體內(nèi)的平均消除半衰期(T1/2)約為15.16 h,平均滯留時(shí)間(MRT)約為2.44 h,藥物從零時(shí)間至24 h的平均藥時(shí)曲線下面積(AUC0～24h)約為1.80 μg·h/mL,平均表觀分布容積(Vd)約為49.78 L/kg,平均血漿清除率(CL)約為2.42 L/(kg·h)。犬單劑量10 mg//kg bw和20 mg/kg bw口服鹽酸特比萘芬片后,特比萘芬在犬體內(nèi)T1/2分別為19.25和18.15 h,平均達(dá)峰時(shí)間(Tmax)分別為1.69和1.88h,平均達(dá)峰濃度(Cmax)分別為0.16和0.32μg/mL,MRT分別為5.22和5.02 h;AUC0～24h分別為0.62和1.09μg·h/mL;按AUC0～24h估算,平均絕對(duì)生物利用度(F0～24h)分別為17.08%和16.59%。結(jié)果表明,特比萘芬在犬體內(nèi)分布廣泛,消除緩慢;犬口服鹽酸特比萘芬片吸收迅速,但吸收不完全;犬單劑量10 mg//kg bw和20 mg/kg bw 口服鹽酸特比萘芬片,達(dá)峰時(shí)間、消除半衰期、平均滯留時(shí)間和生物利用度均無顯著差異,但達(dá)峰濃度和藥時(shí)曲線下面積成比例增加,具劑量相關(guān)性。
[Abstract]:Terbinafine hydrochloride is the second generation broad-spectrum antifungal drug of propenylamine, which has the characteristics of clear antifungal mechanism, wide antifungal spectrum, definite curative effect, multiple dosage forms and wide applicability, and has been widely used in human medicine at present. However, there is still little research on animals. The aim of this study was to obtain the relevant pharmacokinetic parameters by injection of terbinafine hydrochloride injection and oral administration of terbinafine hydrochloride tablets in dogs, and to understand the pharmacokinetics and absolute bioavailability of terbinafine in dogs. Eight healthy Beagle dogs with the same body weight were randomly divided into two groups, 4 in each group (half male and female), and 8 healthy beagle dogs were randomly divided into two groups, 4 in each group (half male and female), and 8 healthy Beagle dogs with consistent weight were randomly divided into two groups, 4 in each group (half male and female). In the first stage, 2% terbinafine hydrochloride was administered intravenously to dogs in the first group (5 mg/kg bw), and the second group was given terbinafine hydrochloride tablets orally at 20 mg/kg bw. In the second stage, a single dose (20 mg/kg bw) of terbinafine hydrochloride tablets was given to dogs in the first group, and a 2% terbinafine hydrochloride injection was injected intravenously in the second group (5 mg/kg bw). The two-stage elution period was 2 weeks. In addition, 8 dogs were given terbinafine hydrochloride tablets at a single dose (10 mg/kg bw) in a parallel lower dose oral administration group. Blood samples were collected at the scheduled time after administration. Terbinafine in plasma was determined by high performance liquid chromatography series diode array detector (HPLC-DAD). The mobile phase consisted of methanol-0.1% phosphoric acid aqueous solution (59 脳 41, V 路V). The external standard method was used for quantitative analysis. The pharmacokinetic parameters of terbinafine were calculated by pharmacokinetic analysis software WinNonlin5.2. After intravenous injection of 2% terbinafine hydrochloride (5 mg/kg bw), the average elimination half life (T 1) of terbinafine was about 15.16 h and the mean retention time (MRT) of terbinafine was about 2.44 h. The average area under the curve (AUC0~24h) of the drug from zero to 24 hours was about 1.80 渭 g 路h / mL, and the average apparent distribution volume (Vd) was about 49.78 L 路kg ~ (- 1). The mean plasma clearance rate (CL) was about 2.42 L / (kg 路h). After oral administration of terbinafine hydrochloride tablets for 10 mg//kg bw and 20 mg/kg bw in dogs, the T _ (1) O _ (2) of terbinafine was 19.25 and 18.15 h, and the average peak time (Tmax) was 1.69 and 1.88 h, respectively, and the mean peak time of terbinafine was 1.69 and 1.88 h respectively. The average peak concentrations (Cmax) were 0.16 渭 g / mL,MRT and 0.32 渭 g / mL,MRT for 5.22 and 5.02 h, respectively. The AUC0~24h values were 0.62 and 1.09 渭 g 路h / mL;, respectively, and the mean absolute bioavailability (F0 / 24h) was 17.08% and 16.59%, respectively, according to AUC0~24h. The results showed that terbinafine was widely distributed in dogs and its elimination was slow, and that terbinafine hydrochloride tablets were absorbed quickly but not completely by oral administration of terbinafine hydrochloride in dogs. There was no significant difference in peak-reaching time, elimination half-life, average retention time and bioavailability of terbinafine hydrochloride tablets at a single dose of 10 mg//kg bw and 20 mg/kg bw in dogs, but the peak concentration and area under the drug-time curve increased proportionally. There was dose-dependent.
【學(xué)位授予單位】：揚(yáng)州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：S859.7
[Abstract]:Terbinafine hydrochloride is the second generation broad-spectrum antifungal drug of propenylamine, which has the characteristics of clear antifungal mechanism, wide antifungal spectrum, definite curative effect, multiple dosage forms and wide applicability, and has been widely used in human medicine at present. However, there is still little research on animals. The aim of this study was to obtain the relevant pharmacokinetic parameters by injection of terbinafine hydrochloride injection and oral administration of terbinafine hydrochloride tablets in dogs, and to understand the pharmacokinetics and absolute bioavailability of terbinafine in dogs. Eight healthy Beagle dogs with the same body weight were randomly divided into two groups, 4 in each group (half male and female), and 8 healthy beagle dogs were randomly divided into two groups, 4 in each group (half male and female), and 8 healthy Beagle dogs with consistent weight were randomly divided into two groups, 4 in each group (half male and female). In the first stage, 2% terbinafine hydrochloride was administered intravenously to dogs in the first group (5 mg/kg bw), and the second group was given terbinafine hydrochloride tablets orally at 20 mg/kg bw. In the second stage, a single dose (20 mg/kg bw) of terbinafine hydrochloride tablets was given to dogs in the first group, and a 2% terbinafine hydrochloride injection was injected intravenously in the second group (5 mg/kg bw). The two-stage elution period was 2 weeks. In addition, 8 dogs were given terbinafine hydrochloride tablets at a single dose (10 mg/kg bw) in a parallel lower dose oral administration group. Blood samples were collected at the scheduled time after administration. Terbinafine in plasma was determined by high performance liquid chromatography series diode array detector (HPLC-DAD). The mobile phase consisted of methanol-0.1% phosphoric acid aqueous solution (59 脳 41, V 路V). The external standard method was used for quantitative analysis. The pharmacokinetic parameters of terbinafine were calculated by pharmacokinetic analysis software WinNonlin5.2. After intravenous injection of 2% terbinafine hydrochloride (5 mg/kg bw), the average elimination half life (T 1) of terbinafine was about 15.16 h and the mean retention time (MRT) of terbinafine was about 2.44 h. The average area under the curve (AUC0~24h) of the drug from zero to 24 hours was about 1.80 渭 g 路h / mL, and the average apparent distribution volume (Vd) was about 49.78 L 路kg ~ (- 1). The mean plasma clearance rate (CL) was about 2.42 L / (kg 路h). After oral administration of terbinafine hydrochloride tablets for 10 mg//kg bw and 20 mg/kg bw in dogs, the T _ (1) O _ (2) of terbinafine was 19.25 and 18.15 h, and the average peak time (Tmax) was 1.69 and 1.88 h, respectively, and the mean peak time of terbinafine was 1.69 and 1.88 h respectively. The average peak concentrations (Cmax) were 0.16 渭 g / mL,MRT and 0.32 渭 g / mL,MRT for 5.22 and 5.02 h, respectively. The AUC0~24h values were 0.62 and 1.09 渭 g 路h / mL;, respectively, and the mean absolute bioavailability (F0 / 24h) was 17.08% and 16.59%, respectively, according to AUC0~24h. The results showed that terbinafine was widely distributed in dogs and its elimination was slow, and that terbinafine hydrochloride tablets were absorbed quickly but not completely by oral administration of terbinafine hydrochloride in dogs. There was no significant difference in peak-reaching time, elimination half-life, average retention time and bioavailability of terbinafine hydrochloride tablets at a single dose of 10 mg//kg bw and 20 mg/kg bw in dogs, but the peak concentration and area under the drug-time curve increased proportionally. There was dose-dependent.
【學(xué)位授予單位】：揚(yáng)州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：S859.7
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